The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Angina pectoris (‘tight chest’) is chest pain due to lack of oxygen in the myocardium. The lack of oxygen is normally due to ischaemia, a reduction in blood supply (and, hence, oxygen supply) to the myocardium. Normally this ischaemia is caused by atherosclerotic plaques in the coronary vessels, but it can also be caused by a local spasm in the coronary vasculature. Other rare causes can be valve disease, severe anemia, aortic stenoses and tachyarrythmias. Angina pectoris is divided into effort angina, angina triggered by physical and/or mental exertion; spasm-angina (variant or Prinzmetal's angina), sudden angina without correlation to a specific situation; and syndrome X, typically an effort related angina but without overt stenosis on angiography. An angina attack normally has a duration of 1 to 5 minutes. If attacks occur at rest, or have a duration exceeding 15 minutes, the disease is referred to as unstable angina and is associated to imminent risk of a cardiovascular event. The condition is classified as unstable angina also when stable angina symptoms are worsened. Unstable angina belongs to the Acute Coronary Syndrome (ACS) and is a critical condition. A myocardial infarction is normally caused by almost complete absence of blood supply to a part of the myocardium, normally caused by the rupture of a coronary atherosclerotic lesion with a subsequent formation of an occluding thrombus.
Peripheral arterial disease (PAD) is a condition with similarities to angina pectoris, but is present in peripheral arteries, normally the lower extremities. Ischaemic pain is common in these patients, and is also normally associated to physical activity. The pain, or cramping sensation, often experienced as a result of physical exercise in PAD patients is normally referred to as intermittent claudication.
Endothelium in Cardiovascular (CV) Disease.
Vascular dysfunction, in a general sense, characterises most CV disease states, and often involves altered endothelial function. The endothelium is the innermost cell layer in all blood vessels. It is the body's largest endocrine gland, and secretes a number of important factors controlling the circulatory system. Several recent studies have shown that ‘endothelial dysfunction’ is related to an increased risk for CV events [1]. ‘Endothelial dysfunction’ is normally measured as a loss of endothelium mediated dilatation, the capacity the endothelium has to dilate blood vessels in response to certain stimuli [2]. There are several ways to measure endothelium mediated dilatation, the most common is dilation of the brachial artery during hyperemia, flow mediated vasodilatation (FMD) [3]. Using such measurements of endothelium mediated dilatation it is shown that vascular function is hampered in individuals suffering from atherosclerosis related diseases (hypertension, hyperlipidemia, diabetes) [4, 5].
The release of Nitric Oxide, NO, from the endothelium is a key event in endothelium mediated dilatation [6]. The key enzyme in the generation of NO is endothelial nitric oxide synthase, eNOS. It has been mostly studied in direct conjunction to the regulation of the vascular system (thrombosis/haemostasis, blood flow regulation and blood vessel growth), but it is also related to the development of atherosclerosis as well as insulin resistance and/or type 2 diabetes (T2DM). For example, mice deficient in eNOS are more prone to become atherosclerotic than mice with normal eNOS function and are also insulin resistant [7].
Normalisation of vascular (dys-)function in an arterial disease state, measured as restoration of normal endothelium mediated dilatation, may or may not be the result of increased release of NO from the endothelium. Vascular dysfunction may, or may not, result from reduced sensitivity of arterial smooth muscles to the NO and/or may, or may not, result from increased metabolism of the NO that is generated. Other mechanisms can also alter vascular function in arterial disease; for example, it is well known that during vascular inflammation the formation of pro-inflammatory and vasoconstrictor substances are increased, and this could offset vasodilatory effects, such as those caused by NO.
Endothelium in Angina Pectoris and Peripheral Arterial Disease.
When acetylcholine is administered into coronary arteries, it triggers the release of NO from the coronary endothelium, which in turn causes dilatation of the coronaries (endothelium mediated dilatation). When this procedure was performed in patients with coronary artery disease, they responded with a ‘paradoxical vasoconstriction’ [8]. Since then, it has been shown that there is an inappropriate loss of endothelium mediated dilatation in patients suffering from any form of angina pectoris [9, 10], and that this altered function is an important contributor to myocardial ischaemia and, hence, angina pain in these patients.
PAD (normally measured as the reduction in ankle-brachial index (ABI) due to stenosing atherosclerotic lesions) is also characterized by a reduction in endothelium mediated dilatation [11]. In patients where the disease is symptomatic (intermittent claudication) the reduction in endothelium mediated dilatation is greater than in non-symptomatic patients [12].
Systolic hypertension is an important disease in ageing populations, and is normally associated to increased stiffness of the central arterial compartment [13]. It is also shown that NO reduces stiffness [14], and an agent that can restore reduced endothelium mediated dilatation to normal in a patient with systolic hypertension can thus be of therapeutic value.
Another interesting observation is that patients suffering from migraine also have impaired endothelium mediated dilatation, and it was suggested that vascular vasomotion abnormalities can be an important pathophysiological factor in migraine [15, 16]. It is in this context interesting that a mutation in the eNOS gene that is associated to loss of function [17] and is associated to increased risk for CV events [18-20], is also associated to migraine [21].
In yet another aspect of the role of endothelium and NO in disease, erectile dysfunction is also associated with impaired endothelium mediated dilatation [22], and restoring normal endothelium mediated dilatation may also improve erectile dysfunction.
From the above summary, it becomes evident that restoring normal endothelial control of vascular tone by normalising endothelial NO metabolism is a therapeutic opportunity in disease conditions where endothelium mediated dilatation is reduced.
As described above, endothelium mediated dilatation is an important factor in the development of arterial disease. It is also well known that these diseases are also linked to alterations in the haemostatic system, and that vascular inflammation is associated to a state where there is increased risk for arterial thrombus formation.
Annexin A5 is an endogenous protein that binds to charged phospholipids such as phosphatidylserine (PS) [23]. Annexin A5 is a potent anti-thrombotic agent [24], and it is proposed that Annexin A5 by binding to exposed PS can form a ‘protective shield’ that can inhibit the effects of PS on thrombosis formation [25]. It is interesting in this context that in patients with autoimmune disorders such as APS and/or SLE, there are antibodies in the plasma that can reduce the binding of Annexin A5 to PS on e.g. endothelial cell surfaces, thereby increasing PS exposure. This finding may explain why these patients are at a higher risk for thrombotic events than the general population [23]. Very interestingly, there was a significant reduction in Annexin A5 binding capacity to endothelial cells of serum from controls to SLE patients that had not suffered thrombotic events to SLE patients that had suffered such events [26].
It has been shown that in addition to anti-platelet and anti-coagulant effects of Annexin A5, this protein and an analogue thereof, the Annexin A5 dimer diannexin, is effective in preventing against reperfusion injury in the liver [27], and it improved the outcome of rat liver transplants [28]. Interestingly, in both these studies the treatments were associated with a reduced inflammatory activity in the hepatic endothelium, measured as reduced expression of adhesion molecules. It was suggested that diannexin improved the survival of the liver transplants by an anti-thrombotic effect leading to maintained blood supply to the liver [28].
It has earlier been suggested that Annexin A5 can be used to stabilise atherosclerotic lesions in coronary arteries in patients, which should reduce the risk for myocardial infarction in these patients ([26]; WO 2005/099744).